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@INPROCEEDINGS{Pasternak:283071,
      author       = {Pasternak, Maurice and Mirza, Saira S and Paterson, Andrew
                      D and Tartaglia, Carmela and Mitchell, Sara and Black,
                      Sandra E and Freedman, Morris and Tang-Wai, David F and
                      Rogaeva, Ekaterina and Cash, David M and Bocchetta, Martina
                      and van Swieten, John and Laforce, Robert and Tagliavini,
                      Fabrizio and Borroni, Barbara and Galimberti, Daniela and
                      Rowe, James B and Graff, Caroline and Finger, Elizabeth and
                      Sorbi, Sandro and de Mendonça, Alexandre and Butler,
                      Christopher and Gerhard, Alexander and Sánchez-Valle,
                      Raquel and Moreno, Fermin and Synofzik, Matthis and
                      Vandenberghe, Rik and Ducharme, Simon and Levin, Johannes
                      and Otto, Markus and Santana, Isabel and Rohrer, Jonathan D
                      and Masellis, Mario},
      collaboration = {GENFI},
      title        = {{TMEM}106{B} modulates disease severity in genetic
                      frontotemporal dementia phenoconverters},
      journal      = {Alzheimer's and dementia},
      volume       = {21 Suppl 2},
      number       = {Suppl 2},
      issn         = {1552-5260},
      reportid     = {DZNE-2025-01478},
      pages        = {e103532},
      year         = {2025},
      abstract     = {A common variant within TMEM106B is associated with risk
                      for Frontotemporal Lobar Degeneration-Tar DNA binding
                      Protein-43 (FTLD-TDP). A recent study has shown that the
                      minor allele G of TMEM106B-rs1990622 confers protection
                      against FTLD-TDP in symptomatic mutation carriers through
                      reductions in NfL serum levels, brain atrophy, and cognitive
                      decline. It is unknown whether this protective effect is
                      present in phenoconverters of the disease.We included 518
                      participants from the GENetic Frontotemporal dementia
                      Initiative (GENFI), which recruits genetic FTD cases and
                      their family members, both carriers and non-carriers of FTD
                      mutations. Of these, 21 were phenoconverters, 209 were
                      non-carrier controls, 70 were presymptomatic and 45
                      symptomatic C9orf72 carriers, 92 presymptomatic and 29
                      symptomatic GRN carriers, and 39 presymptomatic and 13
                      symptomatic MAPT carriers. Effects of interaction between
                      TMEM106B-rs1990622 and phenoconverter status were examined
                      using mixed effects models, with a random effects structure
                      featuring subjects nested within families and fixed effects
                      for age at baseline and sex. Serum neurofilament light chain
                      (NfL) was measured using the Simoa platform. Cognitive
                      assessment included the Mini-Mental State Examination
                      (MMSE), tests of attention, processing speed, executive
                      function, and language, as well as the Cambridge Behavioural
                      Inventory (CBI), with mixed effects also including years of
                      education as a covariate. Brain volumetry was assessed using
                      T1-weighted MRI and these mixed effect models also included
                      additional covariates of total intracranial volume and
                      scanner site.In phenoconverters, each copy of the protective
                      allele G was associated with a significant reduction in the
                      rate of serum NfL accumulation (-5.33 pg/mL/year; p = 7.79
                      × 10-9). Structural imaging analyses revealed decreased
                      rates of atrophy in fronto-orbital regions and the insular
                      cortex among protective allele carriers. Cognitive
                      trajectories showed significantly slower decline across
                      multiple domains including general cognition (MMSE; p =
                      0.003), attention and processing speed (p = 2.2 × 10-4),
                      executive function (p = 2.6 × 10-7), language (p = 2.9 ×
                      10-3), and behavioural symptoms as measured by CBI (p = 9.5
                      × 10-3).The TMEM106B-rs1990622 protective variant
                      significantly modulates disease progression in genetic FTD
                      phenoconverters across multiple markers, suggesting its
                      potential as a therapeutic target.},
      month         = {Jul},
      date          = {2025-07-27},
      organization  = {Alzheimer’s Association
                       International Conference, Toronto
                       (Canada), 27 Jul 2025 - 31 Jul 2025},
      keywords     = {Humans / Male / Female / Nerve Tissue Proteins: genetics /
                      Middle Aged / Biomarkers: blood / Membrane Proteins:
                      genetics / Frontotemporal Dementia: genetics /
                      Frontotemporal Dementia: pathology / Aged / C9orf72 Protein:
                      genetics / Brain: pathology / Brain: diagnostic imaging /
                      tau Proteins: genetics / Progranulins: genetics /
                      Neurofilament Proteins: blood / Mutation: genetics /
                      Magnetic Resonance Imaging / Atrophy / Nerve Tissue Proteins
                      (NLM Chemicals) / Biomarkers (NLM Chemicals) / TMEM106B
                      protein, human (NLM Chemicals) / Membrane Proteins (NLM
                      Chemicals) / C9orf72 Protein (NLM Chemicals) / tau Proteins
                      (NLM Chemicals) / Progranulins (NLM Chemicals) /
                      Neurofilament Proteins (NLM Chemicals) / C9orf72 protein,
                      human (NLM Chemicals) / MAPT protein, human (NLM Chemicals)
                      / neurofilament protein L (NLM Chemicals)},
      cin          = {AG Gasser / Clinical Research (Munich) / AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1111015 /
                      I:(DE-2719)1111016},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      pubmed       = {pmid:41449512},
      pmc          = {pmc:PMC12741048},
      doi          = {10.1002/alz70856_103532},
      url          = {https://pub.dzne.de/record/283071},
}